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First in Man Study Investigating the Biodistribution, the Safety and Optimal Recommended Dose of a New Radiolabelled Monoclonal Antibody Targeting Frizzled Homolog 10 (FZD10) in Patients With Relapsed or Refractory Non Resectable Synovial Sarcomas

Phase 1
18 Years
Open (Enrolling)
Sarcoma, Synovial

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Trial Information

First in Man Study Investigating the Biodistribution, the Safety and Optimal Recommended Dose of a New Radiolabelled Monoclonal Antibody Targeting Frizzled Homolog 10 (FZD10) in Patients With Relapsed or Refractory Non Resectable Synovial Sarcomas

PART 1: Imaging with OTSA101 DTPA-111In OTSA101-DTPA-111In (1.5mg OTSA101-DTPA radiolabeled
with 185 MBq of 11In) will be administered intravenously (IV) as a single injection on Day
-28 (D-28). Patients will undergo serial anterior-posterior gamma scans and single photon
emission computed tomography (SPECT/CT) at 1, 2, 5, 24, 48, 72, 144 hours post-dosing to
estimate absorbed radiation doses to tumor, to normal organs (i.e., liver, lung, kidney, and
bone marrow), and whole body in order to determine OTSA101-DTPA-111In tumor uptake (ID%/g [%
of injected dose (ID) per gram of tumor]) and biodistribution (ratio tumor/normal tissue of
estimated radiation-absorbed dose). PK sampling will be performed at the same time points
with additional sampling at D-14 and D0.

A Steering Committee meeting is planned at the end of PART 1 for each patient. The Steering
Committee will evaluate on a case by case basis at Day -7 for each patient if he/she can
proceed to the therapeutic part based on tumor targeting, biodistribution, safety and
clinical assessments:

- Patients with expected biodistribution and tumor uptake, no safety concerns and no
overt signs of disease progression will proceed to the therapeutic part of the study
after validation by the Steering Committee.

- Patients displaying abnormal/unexpected biodistribution of OTSA101-DTPA-111In, safety
concerns and/or overt sign of disease progression will be taken off the study and other
therapeutic plan will be envisaged.

PART 2: Therapeutic dose of OTSA101-DTPA-90Y OTSA101-DTPA-90Y will be administered IV as a
single injection on Day 0 (i.e. 28 days after the injection of OTSA101-DTPA-111In - A
1week-delay [i.e. +7 days] is authorized from the planned D0).

Twelve (12) patients should be randomized in the PART 2 and treated with OTSA101-DTPA-90Y at
two initial dose levels (6 patients per dose level):

- Arm A: 1.5 mg of OTSA101-DTPA radiolabeled with 370MBq of 90Y (Dose level 1 (DL1)

- Arm B: 1.5 mg of OTSA101-DTPA radiolabeled with 1110 MBq of 90Y (Dose level 2 (DL2)

Based on safety and preliminary efficacy data, a third dose level will be evaluated in 6
additional patients:

- Arm C: 3 mg of OTSA101-DTPA radiolabeled with 2220 MBq of 90Y (Dose level 3 (DL3).

Such a study design will allow the determination of an optimal and recommended dose,
surrounded by a lower suboptimal dose and a higher maximal tolerated (or possibly toxic)

The first 3 patients will be enrolled at Centre Léon Bérard. Following the randomization of
the first 2 patients, the accrual will be stopped for a maximal period of 1 month. The
safety data will be reviewed every 2 randomized patients. Thee benefit/risk ratio will be
regularly reviewed by the iDSMB and the Steering Committee (See Section Study Committee).

A compassionate program is planned for all randomized patients who derive clinical benefit
from the study drug (at least stable disease and acceptable tolerance). A maximum of 4
injections per year will be planned. Subsequent injection will be performed provided that
the eligibility criteria (except criteria related to previous treatment) are met before the
day of administration. All inclusion in the compassionate program will be validated by the
Steering Committee.

Inclusion Criteria:

- Male or female patients, age ≥ 18 years.

- Histologically confirmed progressive synovial sarcoma with a minimal total tumor
volume of 65mL at the time of inclusion.

- Frozen or paraffin-embedded tumor samples for immunohistochemical analysis are
mandatory for registration in this study.

- Patients with doxorubicin- and ifosfamide-resistant synovial sarcoma (defined as
patients with progression under doxorubicin and ifosfamide treatments or with rapid
progression (i.e. within 4 months) after the last dose of doxorubicin and ifosfamide,
or patients previously treated with doxorubicin and ifosfamide and with disease
progression on another regimen of chemotherapy for advanced disease).

- Patients must have disease not amenable to surgery, radiation or combined modality
treatment with curative intent.

- At least one measurable site of disease as defined by RECIST criteria 1.1.

- ECOG performance status of 0, 1, 2.

- Life expectancy ≥ 3 months.

- Left Ventricular Ejection Fraction (LVEF)> 50% as assessed by MUGA scan or ECHO at

- Normal pulmonary function with Force Vital Capacity (FVC) of at least 60% and DLCO of
at least 50%.

- Adequate bone marrow, liver and renal function including the following:

- Absolute neutrophil count ≥ 1.5 G/L, platelet count ≥ 100 G/L, and hemoglobin ≥
10 g/dL)

- AST/ALT ≤ 3 x upper limit of normal (ULN) (or ≤ 5.0 x ULN if liver metastasis)
and total bilirubin ≤ 1.5 x ULN (≤ 2.5 x ULN if liver metastases),

- Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min according to
Cockroft formula.

- Adequate contraceptive methods for the whole duration of the study and for up to 12
months after the last study drug administration.

- Mandatory affiliation with a health insurance company.

- Patients must provide written informed consent before any study specific procedures
or assessments, and must be willing to comply with follow up assessments and

Exclusion Criteria:

- Chemotherapy within the last 4 weeks before inclusion; radiotherapy, or any other
investigational agent within 14 days or 5 half-lives, whichever is longer prior to
the first dose of study drug.

- Positive human anti-mouse antibody (HAMA) or human anti-chimeric antibody (HACA)
response. HAMA/HACA assays will be performed only for patients previously treated by
monoclonal antibodies.

- Uncontrolled arterial hypertension: systolic blood pressure ≥ 140 mmHg or diastolic
blood pressure ≥ 90 mmHg or both despite appropriate therapy.

- Patients with brain metastases.

- Previous history of high-dose chemotherapy with stem cell rescue.

- Chronic use of immunosuppressive drugs such as systemic corticosteroids.

- Previous therapy with monoclonal antibodies within 4 months before study entry.

- Clinically significant abnormal ECG (i.e. > grade 1) at inclusion.

- Prior history of other malignancies other than synovial sarcoma (except for basal
cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix)
unless the subjects has been free of the disease for at least 3 years.

- No resolution of all specific toxicities (excluding alopecia) related to any prior
anti-cancer therapy to Grade ≤ 1 according to the NCI CTCAE v4.

- Known immediate or delayed hypersensitivity reaction to 111In, 90Y, DTPA or any
excipients of the investigational product.

- Psychological, familial, sociological, or geographical conditions that would limit
compliance with study protocol requirements.

- Pregnant and breastfeeding women are ineligible.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Part 1: Biodistribution and binding of OTSA101-DTPA-111In

Outcome Description:

Limiting Event is defined as unacceptable/unexpected biodistribution/binding of the mAb, and/or absence of tumor uptake. Data review will be performed on a patient per patient basis. The Biodistribution and binding of OTSA101-DTPA-111In will be analyzed. The rate of Limiting Event will be summarized by a proportion together with its 95% confidence interval.

Outcome Time Frame:

144 hours post-dose (dose administered at day -28)

Safety Issue:


Principal Investigator

Jean-Yves BLAY, MD, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Centre Léon Bérard


France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Study ID:




Start Date:

December 2011

Completion Date:

December 2013

Related Keywords:

  • Sarcoma, Synovial
  • cancer
  • relapse or refractory
  • Sarcoma, Synovial
  • Sarcoma