First in Man Study Investigating the Biodistribution, the Safety and Optimal Recommended Dose of a New Radiolabelled Monoclonal Antibody Targeting Frizzled Homolog 10 (SYNFRIZZ)
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.
Drug: OTSA101-DTPA-90Y level 1
Drug: OTSA101-DTPA-90Y level 2
Drug: OTSA101-DTPA-90Y level 3
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||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: Biodistribution and binding of OTSA101-DTPA-111In [ Time Frame: 144 hours post-dose (dose administered at day -28) ] [ Designated as safety issue: Yes ]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.
- Part 2: Safety profile [ Time Frame: During 1 year after randomization (day 0) ] [ Designated as safety issue: Yes ]
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.
- Part 1: Pharmacokinetics parameters [ Time Frame: They will be collected before the injection, (day -28) at 1, 2, 5, 24, 48, 72, 144 hours post dose and 14 days before randomisation ] [ Designated as safety issue: No ]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.
- Part 1: Safety profile of OTSA101-DTPA-111In [ Time Frame: During 28 days ] [ Designated as safety issue: No ]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.
- Part 2: Overall response rate [ Time Frame: At 6 and 12 weeks after treatment ] [ Designated as safety issue: No ]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.
- Part 2: Clinical benefit [ Time Frame: At 6 and 12 weeks after treatment ] [ Designated as safety issue: No ]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.
- Part 2: Duration of response [ Time Frame: At Week 6; Week12; Month 6; Month 9 and Month12 post Yttrium injection ] [ Designated as safety issue: No ]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.
- Part 2: Pharmacokinetics [ Time Frame: 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 ] [ Designated as safety issue: No ]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.
|Study Start Date:||December 2011|
|Study Completion Date:||June 2015|
|Primary Completion Date:||June 2015 (Final data collection date for primary outcome measure)|
Experimental: Arm A: Dose level 1
1.5 mg of OTSA101-DTPA radiolabelled with 370MBq of 90Y
Drug: OTSA101-DTPA-90Y level 1
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.
Experimental: Arm B: Dose level 2
1.5 mg of OTSA101-DTPA radiolabelled with 1110 MBq of 90Y
Drug: OTSA101-DTPA-90Y level 2
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.
Experimental: Arm C: Dose level 3
3 mg of OTSA101-DTPA radiolabelled with 2220 MBq of 90Y
Drug: OTSA101-DTPA-90Y level 3
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.
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) 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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01469975
|Centre Léon Bérard|
|LYON Cedex 08, France, 69373|
|Principal Investigator:||Jean-Yves BLAY, MD, PhD||Centre Leon Berard|