Conditions: Progressive Desmoids Tumors
Keywords: Desmoids tumors Pazopanib Phase 2 clinical trial Cross over
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 72
Healthy volunteers: no

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.

Arms:
arm 1: 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 arm 2: 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.

Interventions: intervention 1: PAZOPANIB treatment intervention 2: Active Comparator: Vinblastine and Methotrexate
Intervention descriptions: intervention 1: 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 intervention 2: 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.

Protocol document:
Prot_SAP_000.pdf: 
Efficacy and tolerance of pazopanib in desmoid tumors : a randomised phase 2 study 
 
NCT01876082 
 
 
08/19/2016 
 
 


Study Title   
Efficacy and tolerance of pazopanib in desmoid tumors : a randomised 
phase 2 study  
 
Acronym 
DESMOPAZ 
Sponsor 
Institut Bergonié, Bordeaux, France  
Coordinating 
investigator 
Antoine Italiano, MD, PhD  
Département d’oncologie médicale 
Institut Bergonié, Bordeaux 
Sites of 
investigation 
13 Sites : 
- 
Institut Bergonié, Bordeaux  
- 
Centre François Baclesse, Caen 
- 
Centre Georges Francois Leclerc, Dijon 
- 
Centre Oscar Lambret, Lille 
- 
Centre Léon Bérard, Lyon 
- 
Centre René Gauducheau, Nantes 
- 
Centre Antoine Lacassagne, Nice  
- 
Institut Curie, Paris  
- 
Institut Gustave Roussy, Villejuif 
- 
Institut Claudius Régaud, Toulouse 
- 
Institut Paoli Calmettes, Marseille 
- 
Assistance Publique des Hôpitaux de Paris : Hôpital ST Louis 
- 
Assistance Publique des Hôpitaux de Paris - Hôpital Saint Antoine 
- 
Centre Paul Papin – ICO Angers 
 
Study design 
Multicentric Randomised Phase 2 Study (Simon design with 2 steps) 
Number of patients 72 patients (arm pazopanib: 43 patients ; arm méthotrexate-vinblastine : 22 ; + 10 
%)  
Study milestones 
Inclusion of the first patient: September 2012 
Inclusion period: 60 months 
Follow-up: 24 months 
Study duration: 84 months 
Indication 
Adult patients with a progressive desmoid tumor  
Objectifs 
 Main endpoint 
Evaluation of efficacy of: 
- 
pazopanib in terms of non-progression rate at 6 months (RECIST criteria v.1.1) 
- 
methotrexate-vinblastine in terms of non-progression rate at 6 months 
(RECIST criteria v.1.1) 
 
 Secondary endpoints 
For each arm 
- 
Evaluation of efficacy in terms of: 
o 
Best overall response RECIST 
o 
Progression-free survival   
o 
Overall survival  
- 
Evaluation of safety (before each cycle and at the end of treatment)  


- 
Evaluation of pain: D0, before each cycle for the first three months, then every 
three months; at progression of disease and at the end of treatment (Brief 
Pain Inventory) 
- 
Quality of life : D0, before each cycle for the first three months, then every 
three months ; at progression of diease and at the end of treatment (EORTC 
QLQ-C30) 
- 
Pharmacogenomic analysis. 
 
For patients included in arm pazopanib 
- 
Pharmacokinetics: assessment of variability of Cmin concentration of 
pazopanib and correlation with outcome.  
 
 
Inclusion criteria 
Inclusion criteria: 
1) Subjects must provide written informed consent   
2) Age ≥ 18 years or legal age of consent if greater than 18 years 
3) ECOG ≤ 1 
4) Histologically confirmed diagnosis of desmoid tumor (central review) 
5) Documented disease progression (as per RECIST) before study entry with two 
imaging obtained at less than 6 months interval 
6) Patients must have measurable disease (outside any previously irradiated field) 
defined as at least one lesion that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as >20 mm with conventional 
techniques or as >10 mm with spiral CT scan.   
7) Normal LVEF  
8) Adequate organ system function as defined in Table 1 
Table 1: Definitions for Adequate Organ Function 
System 
Laboratory Values 
Hematology 
Absolute neutrophil count (ANC) 
1.5 X 109/L 
Hemoglobina  
9 g/dL (5.6 mmol/L) 
Platelets 
100 X 109/L 
Prothrombin time (PT) or international normalized 
ratio (INR)b  
1.2 X ULN 
Activated partial thromboplastin time (aPTT) 
1.2 X ULN 
Hepatic 
Total bilirubin 
1.5 X ULN  
Alanine amino transferase (ALT) and Aspartate 
aminotransferase (AST)c  
2.5 X ULN 
Renal 
Serum creatinine 
1.5 mg/dL (133 µmol/L) 


Or, if >1.5 mg/dL: Calculated creatinine clearance 
(ClCR) (appropriate appendix) 
50 mL/min 
Urine Protein to Creatinine Ratio (UPC; 
appropriate appendix)d  
<1 
a. Subjects may not have had a transfusion within 7 days of screening assessment. 
b. Subjects receiving anticoagulant therapy are eligible if their INR is stable and 
within the recommended range for the desired level of anticoagulation. 
c. Concomitant elevations in bilirubin and AST/ALT above 1.0 x ULN (upper limit of 
normal) are not permitted. 
d. If UPC 1, then a 24-hour urine protein must be assessed.  Subjects must have a 24-
hour urine protein value <1 g to be eligible. 
9)A female is eligible to enter and participate in this study if she is of: 
a. Non-childbearing potential (i.e., physiologically incapable of 
becoming pregnant), including any female who has had: 
 A hysterectomy 
 A bilateral oophorectomy (ovariectomy) 
 A bilateral tubal ligation 
 Is post-menopausal 
Subjects not using hormone replacement therapy (HRT) must have 
experienced total cessation of menses for ≥ 1 year and be greater than 45 
years in age, OR, in questionable cases, have a follicle stimulating hormone 
(FSH) value >40 mIU/mL and an estradiol value < 40pg/mL (<140 pmol/L).  
Subjects using HRT must have experienced total cessation of menses for >= 
1 year and be greater than 45 years of age OR have had documented 
evidence of menopause based on FSH and estradiol concentrations prior to 
initiation of HRT 
b. Childbearing potential, including any female who has had a negative 
serum pregnancy test within a week prior to the first dose of study 
treatment, preferably as close to the first dose as possible, and 
agrees to use adequate contraception.   
Acceptable contraceptive methods, when used consistently and in 
accordance with both the product label and the instructions of the 
physician, are as follow: 
 
Complete abstinence from sexual intercourse for 14 days before exposure 
to investigational product, through the dosing period, and for at least 21 
days after the last dose of investigational product 
 
Oral contraceptive, either combined or progestogen alone 
 
Injectable progestogen 
 
Implants of levonorgestrel 
 
Estrogenic vaginal ring  
 
Percutaneous contraceptive patches  
 
Intrauterine device (IUD) or intrauterine system (IUS) with a documented 
failure rate of less than 1% per year 


 
Male partner sterilization (vasectomy with documentation of 
azoospermia) prior to the female subject's entry into the study, and this 
male is the sole partner for that subject   
 
Double barrier method: condom and an occlusive cap (diaphragm or 
cervical/vault caps) with a vaginal spermicidal agent 
(foam/gel/film/cream/suppository) 
Female subjects who are lactating should discontinue nursing prior to the 
first dose of study drug and should refrain from nursing throughout the 
treatment period and for 14 days following the last dose of study drug. 
10. Affiliation to a Social Security System 
Exclusion criteria 
Exclusion Criteria: 
1. Patient with a history of a prior malignancy with the exception of cervical 
intraepithelial neoplasia; basal cell carcinoma of the skin; adequately treated 
localized prostate carcinoma with PSA <1.0 ng/ml; or who has undergone 
potentially curative therapy with no evidence of that disease for two years, 
and who is deemed at low risk for recurrence by his/her treating physician 
2. Prior treatment by pazopanib or methotrexate-vinblastine 
3. Allergy to pazopanib, methotrexate or vinblastine 
4. Tumor tissue sample not available for pathological review and/or correlative 
studies.  
5. Clinically significant gastrointestinal abnormalities that may increase the risk 
for gastrointestinal bleeding including, but not limited to: 
• 
Known intraluminal tumor with risk of bleeding 
• 
Inflammatory bowel disease (e.g. ulcerative colitis, Crohn’s disease), or other 
gastrointestinal conditions with increased risk of perforation  
6. Clinically significant gastrointestinal abnormalities that may affect absorption of 
investigational product including, but not limited to: 
• 
Malabsorption syndrome  
• 
Major resection of the stomach or small bowel. 
7. Presence of uncontrolled infection. 
8. Corrected QT interval (QTc) > 480 msecs using Bazett’s formula 
8. History of any one or more of the following cardiovascular conditions within the past 
6 months: 
• 
Cardiac angioplasty or stenting 
• 
Myocardial infarction 
• 
Unstable angina 
• 
Coronary artery bypass graft surgery 
• 
Symptomatic peripheral vascular disease 
10. Class II, III or IV congestive heart failure, as defined by the New York Heart 
Association (NYHA)  
11. Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥140 
mmHg or diastolic blood pressure (DBP) of ≥ 90mmHg]. 
Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to 
study entry.  BP must be re-assessed on two occasions that are separated by a 
minimum of 1 hour; on each of these occasions, the mean (of 3 readings) SBP / DBP 
values from each BP assessment must be <140/90 mmHg in order for a subject to be 
eligible for the study  


12. History of cerebrovascular accident including transient ischemic attack (TIA), 
pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 
months. 
Note: Subjects with recent DVT who have been treated with therapeutic anti-
coagulating agents for at least 6 weeks are eligible 
13. Prior major surgery or trauma within 28 days prior to first dose of study drug 
and/or presence of any non-healing wound, fracture, or ulcer (procedures such as 
catheter placement not considered to be major). 
14. Evidence of active bleeding or bleeding diathesis.  
15. Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels 
16. Hemoptysis in excess of 2.5 mL (or one half teaspoon) within 8 weeks of first dose 
of study drug. 
17. 
Respiratory 
impairment, 
asthma, 
emphysema, 
COPD, 
pneumonia, 
pneumothorax, pulmonary injury,  
18. 
Severe renal insufficiency ; 
19. 
Severe liver insufficiency; 
20. 
History of psoriasis, rhumatoïd arthritis, alcoolism, 
21. Any serious and/or unstable pre-existing medical, psychiatric, or other condition 
that could interfere with subject’s safety, provision of informed consent, or compliance 
to study procedures.  
22. Unable or unwilling to discontinue use of prohibited medications for at least 14 
days or five half-lives of a drug prior to the first dose of study drug and for the duration 
of the study. 
23. Treatment with any of the following anti-cancer therapies:  
• 
radiation therapy, surgery or tumor embolization within 14 days prior to the 
first dose of pazopanib OR 
• 
chemotherapy, immunotherapy, biologic therapy, investigational therapy or 
hormonal therapy within 14 days or five half-lives of a drug (whichever is longer) prior 
to the first dose of Pazopanib 
24. Any ongoing toxicity from prior anti-tumor therapy that is >Grade 1 and/or that is 
progressing in severity, except alopecia. 
25. Pregnancy or breast feeding 
26. Concomitant therapy that can not be discontinued or substituted and is a 
contraindication to methotrexate: 
a. Probenecid (alone or in combination with sulfamethoxazole), 
b. Trimethoprim, 
c. Acetylsalicylic acid (for doses of methotrexate greater than 20 mg per week and 
with acetylsalicylic acid used at analgesic or antipyretic doses (≥ 500 mg per dose and 
/ or <3 g daily) or anti-inflammatory (≥ 1 g per dose and / or> 3 g per day), 
d. Phenylbutazone. 
e. Yellow fever vaccine 


 
Treatment plan 
 
- 
Arm A : Pazopanib 800 mg orally once daily without food (at least 1 hour 
before or 2 hours after a meal) until disease progression with a maximum of 
12 months of treatment.  
- 
Arm B : vinblastine 5 mg/m², méthotrexate 30 mg/m² IV (D1, D8, D15, D21, 
for the first 6 months and D1,D15 after 6 months) 28 days cycle, until disease 
progression and for a maximum of 12 months. 
 
 In case of disease progression according to RECIST criteria: 
. Patients initially included in arm A will have the possibility to receive arm B treatment 
or to stop study participation  
. Patients initially included in arm B will have the possibility to receive arm A treatment 
or to stop study participation  
 Follow-up of patients   
The baseline assessment should be performed in the two weeks before study drug 
administration (potassium blood level should be assessed during the 24 hours 
before  study drug administration) Baseline radiological assessment should be 
performed during the 4 weeks before first study drug administration. Safety 
evaluation will be performed at every visit : D0, D14±3, D28±5, and then every 
Information and written consent form 
Pré - Inclusion
 
Screening 
Inclusion/Randomisation  
 
J0= day of randomisation 
Bras A 
Pazopanib 800mg/day
 
Bras B
Vinblastine 5 mg/m²,
Methotrexate 30 mg/m² 
Follow Up 
Safety 
Efficacy 
Evaluation of efficacy in terms of 
non-progression rate at 6 months (RECIST criteria v.1.1) 
Adult patients with a progressive desmoid tumor
 
Possibility of   
cross over
If documented progression 
  
(RECIST 1.1) 


four weeks; as well as in the case of progression or dose adjustment. 
Tumor radiological assessment should be performed every 12 weeks by using 
RECIST (version 1.1) [Eur L Ca 45 :228-47, 2009].  
Evaluation criteria 
 Main endpoint  
The main endpoint is the non-progression rate at 6 months. A patient will be 
considered as non-progressive if he is alive without progressive disease according to 
RECIST v1.1. criteria at 6 months after the day of randomization.  
In case of cross-over before 6 months, the patients will be considered as progressive. 
Objective response should be confirmed by a radiological evaluation performed at least 
four weeks after the initial assessment.  
Radiological tumor evaluation should be performed by using the same technique all 
along the study.  
A blinded central review by a radiological expert will be performed to assess tumor 
response. The results of this review will be used for the statistical analysis.  
- 
Secondary objective criteria  
- 
The best overall response is defined as the best response observed 
between first study drug administration and the date of progression. In the 
case of cross-over, only the response observed with the first allocated arm will 
be considered.  
- 
The Progression-free survival, at 1 and 2 years, is defined as the interval 
between the date of randomisation and one the first following event: disease 
progression (RECIST v1.1) or death. Data related to patients loss of follow-up 
and without progression will be censored at the date of the last news.   
- 
The overall survival is defined as the interval between the date of 
randomization and the date of death. Data related to patients’ loss of follow-
up and alive will be censored at the date of the last news.   
- 
Safety will be assessed by using the NCICTCAE.  
- 
Pain will be assessed by using the Brief Pain Inventory questionnaire, at D0, 
and each month before the cycle (during the first three months of treatment) 
and then every three months, at progression and at the end of treatment.  
- 
Quality of life is assessed by using the QLQC30 questionnaire (EORTC) at 
D0, and each month before the cycle (during the first three months of 
treatment) and then every three months, at progression and at the end of 
treatment.  
Statistical Analysis  
 Number of patients 
This is a randomized non-comparative 2-arm phase II trial. Two groups of patients will 
be recruited in parallel. As such, each treatment arm will be analysed independently 
without any formal statistical comparison between them. 


 Arm A : pazopanib 
We rely on an optimal two-stage Simon’s design. Based on the following hypotheses:  
- 60% 6-month non-progression rate (null hypothesis),  
- 80% acceptable 6-month non-progression rate (alternative hypothesis),  
- 5% type I error rate,   
- 80% power, 
a total of  43 assessable subjects/arm will be necessary, with 11 assessable subjects 
recruited to the first stage.  
Stage 1: Following the inclusion of the first 11 assessable patients, if 7 or less patients 
are progression-free (complete response, partial response or stable disease),the study 
would be terminated early. Otherwise, the second group of 32 subjects will be 
recruited.  
Stage 2: If at the end of recruitment, 31 patients or more are progression-free (out of 
the 43 evaluable patients), the corresponding treatment would be considered worthy 
of further testing in this disease. 
To be evaluable, a subject must meet the eligibility criteria AND have received at least 
one administration of pazopanib (arm A) or one administration of methotrexate-
vinblastine (arm B). 
 
Arm B methotrexate + vinblastine 
The randomization is based on a 2:1 ratio, with 2 patients in the pazopanib arm for 1 
patient in the standard arm. Given that 43 eligible and evaluable patients are needed 
in the pazopanib arm and from a 2:1 randomization, 22 eligible and evaluable patients 
are needed in the reference arm (methotrexate-vinblastine). 
 
Total inclusions 
A total of 43 eligible and evaluable patients are needed in the pazopanib 
arm and 22 eligible and evaluable patients are needed in the reference arm 
(methotrexate-vinblastine), ie 65 eligible and evaluable patients in total. To 
take into account the inclusion of possible non-evaluable and / or ineligible 
patients (+/- 10%), we plan to include a total of 72 patients. 
 
Statistical analysis 
- Analysis of the first endpoint  
The 6-month non progression rate will be assessed for each arm by using the 
intent to treat population and will be reported with a 95% confidence interval. 
- Analysis of the secondary endpoints  
. The first endpoint will also be assessed by using the per protocol study 
population. 
. The other endpoints related to efficacy (best objective response, overall survival 
and progression-free survival) will be assessed by using the per protocol and 
intent to treat population. 
. The efficacy rates will be calculated and reported for each arm with a 95% 
confidence interval. 


. Overall and Progression-free survivals will be estimated with the Kaplan Meier 
Method. Median survivals will be reported with a 95% confidence interval. The 
median follow-up will be estimated by using the reverse Kaplan Meier method.