First in Man Study Investigating the Biodistribution, the Safety and Optimal Recommended Dose of a New Radiolabelled Monoclonal Antibody Targeting Frizzled Homolog 10

Study Overview
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Brief Summary
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Advanced synovial sarcoma represents an unmet medical need. The gene encoding frizzled homologue 10 (FZD10), a 7-transmenbrane receptor, member of the Wnt signalling receptor family, is overexpressed in SS and is undetectable in normal human tissues except placenta. OncoTherapy Science Inc. has developed a chimeric humanized monoclonal antibody (mAb) against FZD10, named OTSA101. Non-radiolabeled OTSA101 antibody has only weak antagonistic activity on SS cell growth. However, Yttrium 90-radiolabeled OTSA101 (OTSA101-DTPA-90Y) showed significant antitumor activity following a single intravenous injection in mouse xenograft model. This first in man clinical trial (Phase I) in relapsing SS patients resistant to Doxorubicin and ifosfamide will be divided in 2 parts. In Part 1 (imaging part using OTSA101 radiolabelled with Indium 111 [111In]), the biodistribution and tumor uptake of OTSA101-DTPA-111In will be followed using 111In as radiotracer. In Part 2 (therapeutic part with OTSA101 radiolabelled with Yttrium 90 [90Y]), the safety and PK profiles of OTSA101-DTPA-90Y will be determined and preliminary efficacy data will be collected. This first in Man study should allow defining the optimal recommended dose of OTSA101-DTPA-90Y. Patients will be followed during 1 year.

Detailed Description
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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, 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. 14 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) dose. 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.

Official Title
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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

Conditions
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Sarcoma, Synovial

Intervention / Treatment
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* Drug: OTSA101-DTPA-90Y level 1
* Drug: OTSA101-DTPA-90Y level 2
* Drug: OTSA101-DTPA-90Y level 3


Participation Criteria
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Eligibility Criteria
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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 screening. 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 procedures. Exclusion Criteria: Chemotherapy within the last 2 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Dose level 1<br>1.5 mg of OTSA101-DTPA radiolabelled with 370MBq of 90Y | Drug: OTSA101-DTPA-90Y level 1<br>* Part 2 of the study 1.5 mg of OTSA101-DTPA radiolabelled with 370MBq of 90Y will be administered IV as a single injection on Day 0.<br>|
| Experimental: Arm B: Dose level 2<br>1.5 mg of OTSA101-DTPA radiolabelled with 1110 MBq of 90Y | Drug: OTSA101-DTPA-90Y level 2<br>* Part 2 of the study 1.5 mg of OTSA101-DTPA radiolabelled with 1110 MBq of 90Y will be administered IV as a single injection on Day 0.<br>|
| Experimental: Arm C: Dose level 3<br>3 mg of OTSA101-DTPA radiolabelled with 2220 MBq of 90Y | Drug: OTSA101-DTPA-90Y level 3<br>* Part 2 of the study 3 mg of OTSA101-DTPA radiolabelled with 2220 MBq of 90Y will be administered IV as a single injection on Day 0. This third dose level evaluation will be based on safety and preliminary efficacy data.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Biodistribution and binding of OTSA101-DTPA-111In | 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. | 144 hours post-dose (dose administered at day -14) | 
| Part 2: Safety profile | The safety profile will be summarized with descriptive statistics including the following: Occurrence of Severe Toxicities during the first 8 weeks post-injection of OTSA101-DTPA-90Y. Occurrence of adverse events and serious adverse events during the study treatment period, including laboratory abnormalities, according to CTCAE v4.0 criteria. Optimal recommended dose, defined as the dose level of OTSA101-DTPA-90Y with the best benefice-risk ratio taking into account the preliminary efficacy and safety data. | During 1 year after randomization (day 0) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Pharmacokinetics parameters | The following PK parameters will be collected: Cmax, tmax, t½: terminal half-life; AUC, Cl, Vss: Volume of distribution. These PK parameters will be calculated using non-compartmental analysis. | They will be collected before the injection, (day -14) at 1, 2, 5, 24, 48, 72, 144 hours post dose and 7 days before randomisation | 
| Part 1: Safety profile of OTSA101-DTPA-111In | The safety profile of OTSA101-DTPA-111In will be summarized with descriptive statistics. The occurrence of adverse events and serious adverse events during the whole imaging part, including laboratory abnormalities, will be summarized by a proportion together with its 95% confidence interval. | During 14 days | 
| Part 2: Overall response rate | The overall response rate is defined as the proportion of patients with a complete response or partial response on target lesions according to RECIST 1.1 criteria. | At 6 and 12 weeks after treatment | 
| Part 2: Clinical benefit | The clinical benefit rate is defined as the proportion of patients with a complete response or partial response or a stable disease on target lesions according to RECIST 1.1 criteria. | At 6 and 12 weeks after treatment | 
| Part 2: Duration of response | The duration of clinical response, measured from the time of first documented response until the first documented disease progression or death due to underlying cancer, will be described in responding subjects using descriptive statistics. | At Week 6; Week12; Month 6; Month 9 and Month12 post Yttrium injection | 
| Part 2: Pharmacokinetics | The following parameters will be collected: Cmax, tmax, t½: terminal half-life; AUC, Cl, Vss: Volume of distribution. Pharmacokinetics will be presented as descriptive statistics. Dose proportionality will be evaluated when applicable by an ANOVA mixed model. Accumulation will be assessed by Wilcoxon signed rank test. | They will be collected before the injection, (day 0) at 1, 5, 24, 48 hours post dose and 14, 28 days post dose and at the end of the study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cancer, relapse or refractory