Progressive Desmoids Tumors
Conditions
Keywords
Desmoids tumors, Pazopanib, Phase 2 clinical trial, Cross over
Brief summary
Desmoids tumors are benign soft tissues tumors characterized by aggressiveness and potential local recurrence. There is a female predominance with a sex ratio of 2/1 and median age at diagnosis is about 30 years. Only a complete surgical excision is recommended in desmoids tumors. Some forms of desmoid tumors are recurrent and/or symptomatic and are not accessible to a conservative surgical treatment. In these clinical situations, only a medical treatment may achieve tumor control and quality of life maintenance. Place of systemic treatments in the management of desmoids tumors is poorly evaluated. Regarding chemotherapy, methotrexate and vinblastine protocol is actually the best evaluated combination, which allowed observing objective response rate between 40 and 75%. Toxicity was mainly marked by the risk of haematological toxicity. Pazopanib is an inhibitor of multi-target tyrosine kinase, in oral form, with selective type receptors -1, -2 and -3 of VEGF receptors on the PDGFA and B, and c-Kit. It is currently under clinical development in humans in the treatment of several tumor types.
Detailed description
This is a Phase II, randomized, multicenter, open label trial, evaluating efficacy and safety of pazopanib versus a chemotherapy protocol combining methotrexate and vinblastine in progressive and symptomatic desmoid tumors. This study will include 72 patients in 15 centers of the French Sarcoma Group. Patients will be treated according to therapeutic strategy allocated by randomization until documented RECIST progression and for a maximum of 12 months : * Arm A = experimental strategy: daily oral administration of pazopanib. * Arm B = reference strategy: methotrexate-vinblastine. In case of documented radiological progression (RECIST criteria): * Patients initially included in arm A will have the opportunity, as determined by the investigator, to receive arm B treatment, or leave the study, * Patients initially included in arm B will have the opportunity, as determined by the investigator, to receive arm A treatment, or leave the study.
Interventions
DRUGPAZOPANIB treatment
Pazopanib * 800 mg per day * oral administration * at least 1 hour before or 2 hours after a meal, * until disease progression or for 12 months maximum
DRUGActive Comparator: Vinblastine and Methotrexate
Active Comparator: Vinblastine and Methotrexate vinblastine 5 mg / m², methotrexate 30 mg / m (J1, J8, J15, J21, 6 months and then J1, J15) 28 days per cycle until disease progression or for 12 months.
Sponsors
Institut Bergonié
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Written consent; 2. Age ≥ 18 years; 3. ECOG ≤ 1; 4. Histologically confirmed desmoid tumor; 5. Disease progression before the patient's inclusion : completion of two similar imaging obtained within 6 months apart (a tolerance of 6 weeks is accepted) 6. Measurable target lesion (RECIST criteria) ; 7. Left ventricular ejection fraction (MUGA or ECHO) within the normal; 8. Normal hematological, renal and liver functions : 1. Hemoglobin ≥ 9 g / dl; neutrophils ≥ 1.5 x 109 / l; platelets ≥ 100 x 109 / l; prothrombin time or INR1 ≤ 1.2 ULN or activated partial thromboplastin time ≤ 1.2 ULN; 2. Amino alanine transferase and aspartate amino transferase ≤ 2.5 ULN; 3. Total bilirubin ≤ 1.5 ULN; 4. Creatinine ≤ 1.5 mg/dl or, if creatinine\> 1.5 mg/dl, Creatinine clearance ≥ 50 m/min; 5. Urinary protein / urinary creatinine (Pu / Cu) \<1. If PU/Cu ≥ 1, patients must have a proteinuria below 1g/24 h 9. Women are eligible provided they: 1. Physiologically incapable of childbearing (hysterectomy, oophorectomy, bilateral tubal ligation, menopause). 2. Of childbearing age if they have had a negative pregnancy test in the week before the first dose of treatment. 3. Women of childbearing potential and men must agree to take an adequate method of contraception. Permitted contraceptive methods : IUD with a documented failure rate of 1% per year, Partner's vasectomy, complete sex abstinence (for 14 days before inclusion, the test period and after cessation of treatment according to the chemotherapy as described below), dual contraception, oral contraceptives. Effective contraception must be implemented: * Up to 6 months after treatment with vinblastine * Up to 5 months after treatment with Methotrexate for men and up to 3 months after treatment with Methotrexate for women * For the duration of treatment with Pazopanib; 10. Affiliated to a social security system
Exclusion criteria
1. Personal history of malignancy except: 1. Cervical intraepithelial neoplasia; 2. Skin basal cell carcinoma; 3. Treated localized prostate carcinoma with PSA \<1; 4. Neoplasia treated with curative intent, in remission for at least five years and considered at low risk of relapse. 2. Pretreatement by Pazopanib or Methotrexate - vinblastine; 3. Known allergy to Pazopanib, Methotrexate or vinblastine; 4. Histological sampling not available for review or biological study; 5. Clinical abnormalities which may increase the risk of gastric bleeding (not exhaustive list); 1. Gastric tumor with known risk of bleeding; 2. Inflammatory bowel disease or other gastrointestinal disease may increase the risk of gastric perforation. 6. Pathologies that can lead to impaired intestinal absorption (not exhaustive): 1. Malabsorption; 2. Major resection of small intestine or stomach. 7. Active uncontrolled infectious disease; 8. Corrected QT interval\> 480 ms; 9. History of cardiovascular disease in the last 6 months: 1. Cardiac angioplasty; 2. Myocardial infarction; 3. Unstable angina; 4. Bypass surgery; 5. Symptomatic arterial disease. 10. Congestive heart failure grade II, III or IV according to the New York Hearth Association (NYHA) classification; 11. Uncontrolled arterial hypertension (systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg); 12. History of stroke or transient ischemic attack, pulmonary embolism or deep vein thrombosis not treated, within 6 months; 13. History of major surgery or trauma within 28 days prior the first day of treatment, or presence of a wound, fracture or non-healed ulcer; 14. Evidence of active bleeding or bleeding tendency; 15. Known endobronchial lesions and / or infiltrative lesions of the large vessels lung; 16. History of hemoptysis of more than 2.5 ml in the eight weeks preceding the first day of chemotherapy; 17. Pulmonary dysfunction, asthma, emphysema, chronic obstructive pulmonary bronchitis, pneumonia, pneumothorax, pulmonary contusion, hemothorax, distress acute respiratory syndrome, pulmonary fibrosis; 18. Severe renal dysfunction; 19. Severe hepatic dysfunction; 20. History of psoriasis, rheumatoid arthritis, alcoholism, illness or chronic liver dysfunction; 21. Any pre-existing severe or unstable medical or psychiatric condition, or other condition that may interfere with patient safety, the collection of its informed consent or adherence to treatment; 22. Patient who refused or could not stop taking banned drugs for at least 14 days (or 5 half-lives of the drug) before the first day of start of chemotherapy and for the duration of the study; 23. During cancer treatment: 1. Radiotherapy, surgery or tumor embolization within 14 days before the 1st dose of pazobanib (arm A) or chemotherapy methotrexate, vinblastine (arm B); 2. Chemotherapy, immunotherapy, biological treatment, experimental or hormone therapy within 14 days or 5 half-lives of medication before the first day of the pazopanib (arm A) or chemotherapy with methotrexate, vinblastine (arm B). 24. History of cancer treatment toxicity\> grade 1 and / or whose the intensity increases, outside of alopecia. 25. Pregnancy and lactation 26. Concomitant treatment which can't be interrupted or replaced and which is not indicated with methotrexate: 1. Probenecid (alone or associated with sulfamethoxazole), 2. Trimethoprim, 3. Acetylsalicylic acid (for methotrexate doses above 20 mg per week with the acetylsalicylic acid and used at doses analgesics or antipyretics (≥ 500 mg per dose and/or \<3 g per day)or anti-inflammatory (≥ 1 g per dose and / or \> 3 g per day), 4. Phenylbutazone, 5. Yellow fever vaccine.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Remaining Alive and Progression-free at 6 Months as Per RECIST 1.1 After the Day of Randomisation (6-month Non-progression Rate). | 6 months | Percentage of patients remaining alive and progression-free at 6 months as per RECIST 1.1 after the day of randomisation. Progression is defined using New Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of diameters of target lesions (taking as reference the smallest sum on study), or a unequivocal progression of existing non-target lesions, or the appearance of one or more new lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | 1 year | Best overall response is defined as the best response across all time points (RECIST v1.1). The best overall response is determined once all the data for the participant is known. Each patient has been assigned one of the following categories (RECIST 1.1): complete response (disappearance of all target lesions); partial response (\>=30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters); progression (20% increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) and stable disease (nor CR, PR or progression). |
| Progression-free Survival | Randomization to disease progression, or death due to any cause, whichever occurs first; until 2 years after the last patient randomized. | Progression-free survival (PFS) defined as the time from randomization to the first documented progression (as per RECIST v1.1) or death (due to any cause), whichever occurs first. Patients alive and progression free were censored at the date of last follow-up, death, or last patient contact. Progression is assessed as per RECIST v1.1. Progression-free survival is estimated as a function of time using Kaplan-Meier method. 1- and 2-year PFS rates were reported. |
| Overall Survival | Randomization to disease progression, or death due to any cause, whichever occurs first; until 2 years after the last patient randomized. | Overall survival (OS) defined as the time from randomization to death (due to any cause). Patients alive were censored at the date of last follow-up or last patient contact. Overall survival was estimated as a function of time using Kaplan-Meier method.1- and 2-Year OS rates were reported. |
Countries
France
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| PAZOPANIB Pazopanib
* 800 mg per day
* oral administration
* at least 1 hour before or 2 hours after a meal,
* until disease progression or for 12 months maximum
PAZOPANIB treatment: Pazopanib
* 800 mg per day
* oral administration
* at least 1 hour before or 2 hours after a meal,
* until disease progression or for 12 months maximum | 48 |
| Vinblastine and Methotrexate vinblastine 5 mg / m², methotrexate 30 mg / m (J1, J8, J15, J21, 6 months and then J1, J15) 28 days per cycle until disease progression or for 12 months.
Active Comparator: Vinblastine and Methotrexate: Active Comparator: Vinblastine and Methotrexate vinblastine 5 mg / m², methotrexate 30 mg / m (J1, J8, J15, J21, 6 months and then J1, J15) 28 days per cycle until disease progression or for 12 months. | 24 |
| Total | 72 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | treatment interruption of more than 21 consecutive days observed in cycle 1 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Vinblastine and Methotrexate | Total | PAZOPANIB |
|---|---|---|---|
| Age, Continuous | 42.5 years | 39.8 years | 35.5 years |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment France | 24 participants | 72 participants | 48 participants |
| Sex: Female, Male Female | 15 Participants | 46 Participants | 31 Participants |
| Sex: Female, Male Male | 9 Participants | 26 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 48 | 0 / 22 |
| other Total, other adverse events | 48 / 48 | 22 / 22 |
| serious Total, serious adverse events | 20 / 48 | 10 / 22 |
Outcome results
Primary
Percentage of Patients Remaining Alive and Progression-free at 6 Months as Per RECIST 1.1 After the Day of Randomisation (6-month Non-progression Rate).
Percentage of patients remaining alive and progression-free at 6 months as per RECIST 1.1 after the day of randomisation. Progression is defined using New Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of diameters of target lesions (taking as reference the smallest sum on study), or a unequivocal progression of existing non-target lesions, or the appearance of one or more new lesions.
Time frame: 6 months
Population: Population evaluable for efficacy included all patients who met eligibility criteria and had received at least one complete cycle or two incomplete cycles of treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PAZOPANIB | Percentage of Patients Remaining Alive and Progression-free at 6 Months as Per RECIST 1.1 After the Day of Randomisation (6-month Non-progression Rate). | 84.8 percentage of participants |
| Vinblastine and Methotrexate | Percentage of Patients Remaining Alive and Progression-free at 6 Months as Per RECIST 1.1 After the Day of Randomisation (6-month Non-progression Rate). | 45.0 percentage of participants |
Secondary
Overall Survival
Overall survival (OS) defined as the time from randomization to death (due to any cause). Patients alive were censored at the date of last follow-up or last patient contact. Overall survival was estimated as a function of time using Kaplan-Meier method.1- and 2-Year OS rates were reported.
Time frame: Randomization to disease progression, or death due to any cause, whichever occurs first; until 2 years after the last patient randomized.
Population: Population evaluable for efficacy included all patients who met eligibility criteria and had received at least one complete cycle or two incomplete cycles of treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PAZOPANIB | Overall Survival | OS rate at 1 year | 100.0 Percentage of participants |
| PAZOPANIB | Overall Survival | OS rate at 2 years | 97.8 Percentage of participants |
| Vinblastine and Methotrexate | Overall Survival | OS rate at 1 year | 100.0 Percentage of participants |
| Vinblastine and Methotrexate | Overall Survival | OS rate at 2 years | 100.0 Percentage of participants |
Secondary
Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1.
Best overall response is defined as the best response across all time points (RECIST v1.1). The best overall response is determined once all the data for the participant is known. Each patient has been assigned one of the following categories (RECIST 1.1): complete response (disappearance of all target lesions); partial response (\>=30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters); progression (20% increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) and stable disease (nor CR, PR or progression).
Time frame: 1 year
Population: Population evaluable for efficacy included all patients who met eligibility criteria and had received at least one complete cycle or two incomplete cycles of treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PAZOPANIB | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Partial response | 41.3 percentage of participants |
| PAZOPANIB | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Progression | 4.4 percentage of participants |
| PAZOPANIB | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Stable disease | 54.4 percentage of participants |
| PAZOPANIB | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Inevaluable for response | 0 percentage of participants |
| PAZOPANIB | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Complete response | 0 percentage of participants |
| Vinblastine and Methotrexate | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Inevaluable for response | 5.0 percentage of participants |
| Vinblastine and Methotrexate | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Complete response | 0 percentage of participants |
| Vinblastine and Methotrexate | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Partial response | 30.0 percentage of participants |
| Vinblastine and Methotrexate | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Stable disease | 45.0 percentage of participants |
| Vinblastine and Methotrexate | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Progression | 20.0 percentage of participants |
Secondary
Progression-free Survival
Progression-free survival (PFS) defined as the time from randomization to the first documented progression (as per RECIST v1.1) or death (due to any cause), whichever occurs first. Patients alive and progression free were censored at the date of last follow-up, death, or last patient contact. Progression is assessed as per RECIST v1.1. Progression-free survival is estimated as a function of time using Kaplan-Meier method. 1- and 2-year PFS rates were reported.
Time frame: Randomization to disease progression, or death due to any cause, whichever occurs first; until 2 years after the last patient randomized.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PAZOPANIB | Progression-free Survival | PFS rate at 1 year | 84.8 percentage of participants |
| PAZOPANIB | Progression-free Survival | PFS rate at 2 years | 65.2 percentage of participants |
| Vinblastine and Methotrexate | Progression-free Survival | PFS rate at 1 year | 68.6 percentage of participants |
| Vinblastine and Methotrexate | Progression-free Survival | PFS rate at 2 years | 68.6 percentage of participants |